Delta-(5-carboxy-2-thienyl)-valeric acid and esters



Patented Mar. 28, 1950 DELTA- (S CARBOXY-Z-THIENYLI VALERIC ACID AND ESTERS Hans Reinhard. Rosenberg, Bound Brook, N. J., and. Carlton Webster Croco, Swarthmore, Pa., assignorsto E. I. du Pont de Ncrhours &- com pany, Wilmington, Del., a corporation of Delai No Drawing. Application Decembcr-6,.1946; Serial-No. 714,642:

6 Claims: (01. 260+329) This invention relates to novel organic compounds;

It an object of this invention. to produce novel organic compounds useful as intermediates for the synthesis of pharmaceuticals. A further object is to produce novel organic compounds particularly adaptedfor use as intermediates in the synthesis of biotin and related compounds. ptherand further important objects of-th'is invention will becomeapparent from the following description;

The novel compounds of this invention may be expressed bythe general formula CH, -CH

X G5\I S 1 wherein X stands for a radical selected from the group consisting oi the" nitrile group and radicals derived therefrom by hydrolysis and alkylation:

in other words, X designates the radicals CN; i

v Our novel series of compounds is closelyin terreIa-ted by a. cognate system ofsynthesis. The material in this synthesis is constituted by the delta- (5 -h-alogeno-2-thienyI-) -a1kyl va-ler- Thus, in. the case of the free diates of copending application of Terry and-"Croce;

Serial No. 637,480, now abandoned. They are prepared in said copen'd ing" application by reacting with a halogen, suchas chlorine, bromine or iodine, upon an alkyl ester-of delta-Z-thienyl- Valerie acid in a suitable solvent, for instance glacial acetic acid. These halogeno compounds, for instance the 5-bromo compounds are first reacted with a metal cyanide; whereby the halogen atom becomes replaced by the CN group. A

suitable metal cyanide for this purpose is cuv pnous cyanide; but alkali-metal cyanides, such as potassium cyanide, may also beused, especially if. a copper compoundis presentin the reaction The next step in the synthesis comprises alkaline hydrolysis of the cyano ester compound lolring under a reflux condenser.

lower by acidification, whereby the free diacid, abovev formulated, is obtained. This. diacid may then beconverted into any desirable lower dialkyl ester, by ordinary methods of alkylation, such as reaction with an alcoholin the presence of anhydrous hydrogen chloride, sulfuric acid, boron trifluoride or other esteriiication catalyst.

Our novel series of compounds are useful as organic intermediates, and are especially fitted as intermediates. for the synthesis of biotin and related compounds. This special fitness arises from the fact that our novel compounds are thi enyl-valeric acid compounds which have only two free positions in the thiophene ring, namely positionsfiand 4. Consequently, if the compound is converted eventual-1y into a diamine compound, the two amino groups become oriented in definite positions, namely positions 3 and 4-. Such d-iaminecompounds, .Whichthereforecon-.- tain their nitrogen. atoms in the same relative positions. as in biotin, may be. converted by appropriate reactions into biotin and also into new biotin-like compounds not found in nature.-

A-first step in this further synthesis, as. illustrated by Example 4: below, is the nitration: oi the" new compounds, producing a compound probably represented by the formulawherein X and Y have the same significance'as above.

Without limiting our invention, the followin examples are given to illustrate our preferred mode. of operation. Parts mentioned are by weight;

Example 1.-Delt a-( 5-c ycmo. 2 th'ienyl) -ethylvalerate A mixture ofi 291 parts of. delta-i5-bromor2- thieny1.)-eth=y1.-valerate, parts of cuprouscyanideand 79 parts of pyridine was heated at FLO- 1.75.? C, for four and one-half. hours While stir- The hot' mass was then. poured. into 900 parts of aqueous hy drochloric acid. (2.4% RC1) and cooled to 0- C. while stirring.v About 440 parts ofbenzene were added. and. the mixture was stirred for one. hour. The whole. charge wasthen filtered toj removeia smallamount of solid. The benzene layer of the filtrate Was separated" and washed with parts of dilute hydrochloric acid. and thenwashe'd with water.. The benzene" solution was dried with: so'- dium sulfate the benzene was, distilled off under vacuum, and the product, a colorless liquid; was vacuum distilled at about 1 mm. The fraction boiling at 147-150 C. was collected and had a refractive index of 1.5178 at 25 C.

l Calculated for Analysls F (111d Noolmsointoo .OCzHs Per Cent PerCent. N 5. 74 5. 9 S 13. 55 13. 5 Br 1. 03

Example 2.DeZta- (-carbozcy-2-thienyl) valeric acid Calculated for Analysls Fmmd noooclmsolneooon N per cent Nil 0 S per cent. 13.77 13.98 Acid N 0.... 477 490 (b) A mixture of 26 parts of delta-(5-bromo- 2-thienyl) -valeric acid, 16 parts of potassium cyanide, 4 parts of copper cyanide, 5'7 parts of water, 25 parts of ethyl alcohol and 6 parts of potassium hydroxide was heated in a closed vessel at 200 C. for ten hours and then heated at 210 C. for ten hours. After the alcohol and ammonia were removed by boiling, the charge was filtered. The filtrate was acidified with hy drochloric acid. The precipitate was removed by filtration and crystallized from 50% ethyl alcohol and then recrystallized twice from water. The white product had a melting range of 168-172 C. Its mixed melting range with the product from part (a) was likewise 168-172" C.

Example 3.-Dz'eth'yl ester of deZta-(5-carbocczi- Z-thz'enyl) -valerz'c acid Dry hydrogen chloride (about 35 parts) was passed into a solution of 67 parts of delta-(5- carboxy-Z-thienyl)-valeric acid in 500 parts of absolute ethyl alcohol and the resulting solution was refluxed for five hours. The charge was poured into 2500 parts of water and 300 parts of benzene were added. After shaking to extract the ester, the benzene layer was separated and washed with dilute sodium carbonate solution to remove any free acid, and then with water. The benzene solution was dried with sodium sulfate. The benzene was distilled off and the residual ester was distilled under a vacuum of about 2 mm., collecting the fraction at 155-l68 C. It presumably constituted the diethyl ester of delta- (5-carboxy-2-thienyl) -valeric acid, and had a refractive index of 1.5050 at 25 C.

Example 4.N2'tration 12 parts of ethyl delta-(5-cyano-2-thienyl) valerate were added slowly to 92 parts of 96% sulfuric acid at 58 C. over a period of ten minutes. 10 parts of mixed acid (33% nitric acid and 67% sulfuric acid) were added slowly to the above solution at 5-9 C., over a period of ten minutes, while stirring, and the mass was then held for minutes longer at 5-8 C. The charge was poured onto ice and the heavy oil was extracted with benzene. The benzene solution was washed with water, then with dilute sodium carbonate solution and finally with water.

H The benzene was removed under vacuum and 10 parts of a reddish oil remained which had the -f0110wing. analysis, and presumably was ethyldelta- (5-cyano-3-nitro-2-thienyl) -valerate.

When the above nitro ester was subjected to saponification with potassium hydroxide and water according to Example 2 (a) above and then acidified, delta (5 cyano 3 nitro 2- thienyl) -va1eric acid was obtained.

It will be understood that the details of the above examples may be varied within wide limits without departing from the spirit of this invention. Thus, in the formation of the cyano derivatives, other alkali cyanides beside potassium cyanide may be used, such as sodium cyanide.

In lieu of the bromo-derivative named in the examples, the iodo-derivative can be used. Likewise, other esters than the ethyl ester may be used, for instance the methyl, propyl, butyl, etc.

In the esterification of the diacid, other alcohols, such as methyl, isopropyl, butyl, etc., may be used. Also, esterifying catalysts other than hydrogen chloride can be used, for instance sulfuric acid, boron trifluoride, etc.

We claim as our invention:

1. A compound of the general formula wherein Y represents the delta radical of a compound selected from the group consisting of normal valeric acid and its alkyl esters, while X stands for a radical of the group consisting of CN, COOH and the lower alkyl esters of COOH.

2. An alkyl ester of delta (5-cyano-2- thienyD-valeric acid.

3. Delta (5-cyano-2-thienyl)-ethyl-valerate. 4. Delta (5-carboxy-2-thienyl)-valeric acid. 5. A dialkyl ester of delta-(5-carboxy-2- thienyl) -valeric acid.

6. The diethyl ester of delta-(5-carbox1y-2- thienyD-valeric acid.

HANS REINHARD ROSENBERG. CARLTON WEBSTER CROCO.

REFERENCES CITED The following references are of record in the file of this patent:

Steinkopf: Die Chemie des Thiophens, Ed

wards Lithoprint, 1941, page 82. 

1. A COMPOUND OF THE GENERAL FORMULA 